Genomics in malaria – an interview with Dyann Wirth

Genomics is increasingly being adopted into both research and clinical settings. Here, we speak to Dyann Wirth from Harvard T.H. Chan School of Public Health (MA, USA), about the use of genomics in the field of malaria, from what it can uncover about the parasite to the hurdles that need to be overcome moving towards elimination.

First could you introduce yourself and tell me a bit about your background?

My name is Dyann Wirth; I’m a Professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health. I trained as a molecular biologist and cell biologist as a graduate student and postdoctoral researcher then when I took up my faculty position at Harvard I became interested in the problem presented by parasites – both the burden of disease and the fascination with these organisms as biological entities – so I focused on parasitic diseases.

All of my recent efforts have focused on malaria with two goals. First, to understand how the parasites survive in the natural setting – what are the natural selective forces on the parasites?  – and second, looking at drugs and drug-resistance as a burden and a barrier to eliminating this disease. I’ve had a lot of interest in using genomics to investigate both of these areas.

Could you just give us an overview of the research you presented at ASM Microbe (7–11 June, GA, USA)?

At ASM Microbe I talked about these two research areas with a real focus on using genomics to understand parasite biology. With the great advances in genomic technologies we now have the ability to analyze infectious organisms in the natural setting – so isolated directly from patients carrying the disease, or mosquitoes that transmit the disease – and this gives us an unprecedented opportunity to understand the parasites.

In the case of malaria, the WHO has set the goal of malaria elimination and eventually eradication, and over the last decade there’s been a significant increase in interventions to prevent malaria transmission and to treat disease. What we’ve been able to demonstrate, in collaboration with Professor Daouda Ndiaye at Cheikh Anta Diop University in Dakar, Senegal, is that this large-scale intervention at the population level has actually led to changes in the parasite population, including severe bottlenecking and reduction in parasite population size. We think that this is both an indicator that the interventions are working and potentially a metric that can be used to understand and map what’s going on as areas move from high malaria transmission, to low malaria transmission, to elimination of a disease. And at ASM Microbe I called for this genomic approach to become the new epidemiological standard.

This is new thinking for malaria but if you think about polio – another major infectious disease that is currently in the final stages of being eliminated – genomics have played an enormous role, particularly in the latter phases. Every single case of polio is sequenced and this allows public health officials to understand where this virus has come from, map the transmission network and understand, in this case, where to put their vaccination efforts. So I think this is a new day for malaria and I’m very hopeful this is going to work.

Then the second thing I spoke about was this notion that the parasite has a fairly rapid evolution in response to new selective forces how we’ve been able to harness these using in vitro methodologies to understand how the parasites become resistant to drugs. In particular I spoke about work in which before a drug is released for treatment of malaria we are able to actually anticipate how rapidly resistance will arise and what types of resistance are likely to occur.

So this methodology might also allow us in the future to choose between different potential new molecules with regards to the propensity of these molecules to select resistant organisms and I went into some detail about how those experiments worked. Again, all of this research is enabled by the availability of relatively low-cost, high-throughput, next-generation sequencing technology and it’s really changed our approach.

How has genomics changed the field of infectious diseases more broadly?

Dramatically! Prior to the advent of genomics the field was quite descriptive, in part because there weren’t readily available in vitro culture systems and although there were some animal models they don’t really reflect the human infection. Genomics has allowed us to gain new insights to the parasite as it infects humans and to look at how it functions in the natural setting.

Although much of my own work is in Plasmodium falciparum, in some ways the potential for genomics to really change the paradigm for understanding P. vivax is just beginning to emerge. For this parasite we don’t have an in vitro culture system, so work on samples isolated from the natural setting – humans or mosquitoes – is critical, but by having new genomic technologies available I am very hopefully that our understanding of P. vivax will be greatly changed.

A similar revolution is occurring in mosquito biology. Only a small subset of even the Anopheles mosquitoes can actually effectively transmit the malaria parasite, and with the sequencing of mosquito genomes we’re beginning to tease out what leads to the ability of mosquitoes to transmit a particular disease. Understanding that competence has been one of the holy grails of intervening at the mosquito level – other than just killing mosquitoes, which has been the strategy to-date – and I think it’s an area where genomics has really changed things.

Finally, in the area of drug-resistance, chloroquine resistance existed for about 40 years before we understood the gene driving that resistance. However, as a result of applying genomic approaches to the study of artemisinin resistance it was a matter of months to a couple of years from the appearance of the first resistant parasite to the discovery of the associated gene – it’s really quite phenomenal in terms of the change in our ability! Moreover, there’s now an early warning diagnostic for the development of artemisinin resistance, whereas by the time the gene for chloroquine was identified the resistance had widely spread because there was no way to detect resistance other than failed treatment. And that’s just one concrete example of how genomics has really revolutionized how we think about disease.

How can techniques such as the genetic manipulation of malaria parasites help us to understand their biology?

Genetic manipulation has existed in Plasmodium for about two decades – my lab was actually the very first lab to express a foreign gene in a Plasmodium parasite in 1993. Since then there’s been lots of development and most recently the CRSIPR/Cas9 system has been integrated in Plasmodium, allowing us to do experiments much more quickly and on a much broader scale.

Again, in the area of drug resistance using genetic technologies, scientists are now able to quickly confirm if the gene they suspect is leading to drug resistance is, in fact, the functional cause of the drug resistance. That’s very important because it also allows us to recognize whether this mechanism is worth further investigation to either try to overcome resistance or to think about introducing different drugs.

In basic science, genetic manipulation has really allowed us to understand more rapidly and in a much deeper way the fundamental mechanisms of the parasite by manipulating its genes – either by mutation or removal, you can start to understand which parts of parasite biology are essential and where you might target either drugs or vaccines.

On the mosquito side, the potential use of gene drive to change natural mosquito populations has generated enormous interest.  Gene drive is introducing a genetic change in a mosquito population – that either alters reproduction or, in the case of malaria, changes the ability of a mosquito population to transmit the parasite – then having that modification spread throughout the population naturally. The feasibility has been demonstrated it the laboratory but challenges remain regarding whether this will be field-deployable, whether this will be stable and whether the mosquito will adapt to overcome the changes introduced. Many questions remain, but gene drive has changed the conversation in terms of being able to modify the biology of the key transmission vector so it can no longer transmit malaria. Whether you crash the mosquito population or change the mosquito so it can no longer effectively transmit disease, this technology could have dramatic impacts on the transmission of malaria.

In your opinion, what are the key hurdles to overcome in this field?

Talking about the goal of malaria elimination, there’s been about a decade, starting in 2007, with a very large ramp up in investment, in insecticide treated nets, in rapid diagnostic tests and in wide-scale distribution of artemisinin combination therapies. As a result of this the overall change in malaria has been quite dramatic – worldwide there’s been approximately a 50% reduction in deaths due to malaria and similar reduction in the number of cases.

However, starting in 2012–2013 this rapid decrease has begun to plateau – I think there are several reasons for this slowing progress but do feel that this demonstrates the notion that distributing the existing tools more effectively probably has reached its natural effectiveness point. Of course, there are countries that have eliminated malaria with the current tools – Sri Lanka and Paraguay, for example – but I think there’s a growing recognition that the burden of disease remains in Sub-Saharan Africa and in India and here progress has not been as good. From a public health standpoint I think we should be focusing on high burden countries, rather the shrinking the map.

What would you like to see in the next 5–10 years, moving towards malaria elimination?

There are several things that I think are going to be important. First, I think a vaccine is important because it has the same impact as having a drug or sleeping under a bed-net but without the need for significant human intervention and behavioral activities. A vaccine could reduce disease burden and mortality, because ultimately half a million children still die from malaria each year.

I think the field has slightly lost sight of this with the RTS,S vaccine as, although it is imperfect, people thought it would be successful. However, it’s very clear considering the RTS,S vaccine in its current form and its possible achievement is not going to completely prevent malaria. So I think research and development on new malaria vaccines is critical.

I think an exciting related technology is monoclonal antibodies, which are rapidly moving forward due to their value in cancer. I think there’s enormous opportunity as these monoclonals can last about 3–6 months, so an intervention could be administered only once at the beginning of the malaria season. In addition, with a vaccine you’re faced with trying to design something that elicits the correct immune response whereas with monoclonal antibodies you already have the correct response – you just need to administer it. So monoclonal antibodies could be a bridge to a long-lasting vaccine.

Another obstacle is drugs – there’s now a much better pipeline thanks to the efforts of the Medicines for Malaria Venture (Geneva, Switzerland), the Bill & Melinda Gates Foundation (WA, USA) and others but in fact there aren’t many drugs ready to deploy. We know resistance has been a problem with every drug that’s been introduced, so perhaps we should be planning on resistance and thinking about how to address it from the beginning, rather than this attitude of ‘wait until it happens.’ I think it’s time for the malaria community to be more proactive in how we approach drug design – we know that the parasite is adept at evolving resistance to drugs that target a single enzyme and the success of artemisinin and chloroquine is probably owing to their broad targeting of the parasite, so I think this is an important area to focus on.

Resistance is also a problem for insecticides – there’s widespread resistance to pyrethroids – the main insecticides used in bednets and in residual house spray. We’re almost in a crisis with lack of new insecticides particularly for bednets so I think that’s an area of focus and a possible reason for this plateauing of progress in malaria.

Finally, I think that in order to reduce transmission a greater understanding of mosquito biology and the mosquito–parasite interaction is critical. These are almost unexplored areas, there are a few groups working to expand knowledge  but compared with many other areas of research it’s quite challenging. Both mosquitoes and malaria parasites are complicated organisms and the host–parasite interaction complicates the problem even further. So I think those are questions that need to be addressed, and ones that are going to continue to challenge us in the next decade.

Any other comments?

This is a fascinating field for people to get involved in and we need more people! There was an influx at around the time that I joined the field in the early- to mid-1980s owing to a call by the WHO through their tropical disease research program to bring modern biology to this disease, which was at the time really quite descriptive and quite clinically based. That was very exciting – I joined the field at that time and there were many breakthroughs.

Now there’s a renewed need for new ideas, such as nanotechnology, artificial intelligence, immunotherapy strategies, to the field and I think we need an influx of new thinking.

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